21-nitrones of 9-halo-pregnenes



ZI-NITRONES OF 9-ILALO-PREGNENES Josef Fried and Josef E. Herz, New Brunswick, NJ., as-

signors to Olin Mathieson Chemical Corporation, New York, N. a corporation of Virginia No Drawing. Application April 2, 1956 Serial No. 575,344

4 Claims. (Cl. 260-397.45)

This application is a continuation-in-part of our parent applications, Ser. No. 434,672, filed June 4, 1954, now Patent No. 2,763,671, and Ser. No. 483,166, filed January 20, 1955 This invention relates to .the synthesis of valuable steroids; and has for its objects the provision of an advantageousv process of preparingisteroids of the pregnene (including. pregnene, allopregnene, pregna'diene, and pregnatriene) series having a 21-aldo or acetalizedi aldo group, a 9a-halo group, and an 1'15-hydroxy or ll-keto group; and of certain new steroids useful in the preparation of said steroids.

The process of this invention essentially comprises: (a) converting a 21-alkanesulfonyloxy-95,115-epoxy steroid of the pregnane series to the corresponding 21-bromo or chloro derivative thereof: (b) converting said 21-brom0 or chloro derivative to the corresponding 21-quateruary ammonium salt; (c) converting said ZI-quaterna'ry ammonium salt to the corresponding 21-nitrone derivative; and (.d) converting the 21-nitrone to the corresponding ZI-aldehyde or 21-acetal derivative.

The new compounds of this invention comprise: '(A) 21-bromo or chloro-95,115-epoXy steroidsof the pregnene series; (B) 21-bromo'or-chloro-9oz halo-115 hydroxy or ll-keto steroids of the pregnene series; (C) 21-quaternary ammo'nium-9a-halo-115-hydroxy or ll-keto steroids of the pregnene series; and (D) 21-nitro'ue-9a-halo- 115-hydroxy or keto steroids of the pregnene series.

For a clearer understanding of the foregoing general and following detailed description of the processes of this invention, reference is made to the following schematic analysis:

CHzOSOiR" CHaX' 0 ice Patented Jan. 5, 1960 larly a lower alkyl such as methyl, ethyl, hexyl, etc. and I is preferably methyl; X is chloro or bromo; X is halo (i.e. iodo, bromo, chloro or fluoro, and, preferably is chloro or fluoro); M is a metal, such as an alkali metal or an alkaline earth metal, the halogen salt of which is soluble in the solvent employed in the indicated reaction,

' and preferably is alkali metal, such as potassium or lithium; T is a. tertiary amine; W is an aromatic radical; and

WhereinB is lower alkyl or benzyl and B is lower alkylene.

95,1 15-epoxy-21-halide, Compounds vA pregnene 95,115 oxido -.21 o1 3,20 dione; A

pregnene 95,115 oxido 17a,21 diol 3,20 dione; A pregnadiene 95,115 oxido 21 ol 3,20 dione; A pregnadiene 95,115 oxido 17oc,21 diol 3,20- dione; A pregnadiene 95,115 oxido 21 ol 3,20- dione; and A pregnadiene 95,115 oxido :,21- diol-3,20-dione. As, disclosed in said application, these starting materials are prepared by reacting the corresponding 21-free oil steroid with an alkanesulfonyl halide under substantially anhydrous conditions.

These starting materials, Compounds A, are then reacted with a metal chloride or bromide (MX), wherein MX is as above-defined. Particularly preferred metal halides are lithium chloride and'lithium bromide. Other utilizable salts include beryllium chloride, calcium chloride, potassiumbromide, calcium bromide and barium bromide; The reaction is preferably carried out at elevated temperature in a substantially anhydrous organic solvent wherein the metal halide is soluble. Such solvents include the lower alkanoic acids (particularly glacial acetic acid), ketones (particularly acetone) and lower alkanols. If the'reaction is conducted in a neutral solvent such as acetone, the product formed is the corresponding B (wherein the halide corresponds to the halogen of the metal halide reactant). If, however, an acidic solvent, such as glacial acetic acid, is used, then the epoxy ring is opened to 3 direct-1y yield the corresponding 11,8-hydroxy-9u,21-dihalide derivative, Compounds C, wherein the halo substituents correspond to the halogen of the metal halide reactant.

Compounds B are then reacted with a hydrogen halide (i.e. hydrofluoric, hydrochloric, hydrobromic, or hydroiodic acid) in a suitable solvent (e.g. chloroform), as disclosed in the application of losef Fried, Serial No. 417,489, filed March 10, 1954, now Patent No. 2,852,511. By this reaction, Compounds C are formed having a 91xhalo and 11;8-hydroxy radical and a 2l-halo substituent corresponding to the sub'stituent in Compound B. The 11 fi-hydroxy group present in Compounds C or the corresponding llfl-hydroxy group present in Compounds D, E, and F, can, if desired, be oxidized to the corresponding keto group in the usual manner, as by treating the steroid with chromic acid in glacial acetic acid. Thus, the first class of novel intermediates of this invention may be represented by the general formula wherein at least one of the positions 1,2; 4,5; and 6,7 is double-bonded (preferably the 1,2 and 6,7 positions are saturated and the 4,5-position is double-bonded), R" is hydrogen, R'" is B-hydroxy, or together R" and R is keto, and R, R, X, X, and Z are as hereinbefore defined.

These compounds may also be prepared directly from the corresponding 21-alkanesulfonyloxy derivatives (steroids which are disclosed in our application, Serial No. 516,333, filed June 17, 1955) by reaction thereof with the metal halide, MX', wherein MX' is as hereinbefore defined, under substantially anhydrous conditions, preferably at an elevated temperature in the presence of an organic solvent for the metal halide (e.g. glacial acetic acid or acetone).

Compounds C can then be converted to Compounds D by reacting with a tertiary base (T) at an elevated temperature. Among the tertiary bases which can be mentioned as examples are the aromatic amines (e.g. pyridine, picolines, lutidines, and quinolines). The resulting quaternary ammonium salts may be represented by the 'following general formula wherein one of the positions 1,2; 4,5; and 6,7 is doublebonded (preferably the 4,5-position is double-bonded and the 1,2 and 6,7 positions are saturated), T represents the tertiary amine and R, R, R", R, X, X, and Z are as hereinbefore defined.

These 2l-quaternary ammonium steroids can also be prepared directly from the corresponding 2l-alkanesulfonyloxy derivatives disclosed in said application, Serial No. 516,333, by reacting the 21-alkanesulfo'nyloxy steroid with the tertiary amine under substantially anhydrous conditions, preferably at elevated temperature (e.g. the reflux temperature of the amine).

In the next step of the process of this invention, the quaternary ammonium halide, Compounds D, are reacted with a nitroso compound, preferably an aromatic nitroso compound (WN O), such as nitroso benzene and pnitroso-dimethylaniline, in the presence of a basic reagent such as potassium bicarbonate. By this procedure, a 21- nitrone, Compound E, is formed. These nitrones are exemplified by those of the following general formula wherein one of the positions 1,2; 4,5; and 6,7 is doublebonded (preferably the 4,5 position is double-bonded) and the 1,2 and 6,7 positions are saturated, R, R, R", R, Z, and X are as hereinbefore defined, and W is an aromatic radical such as phenyl and p-dimethylamino phenyl.

To convert the 2l-nitro'nes, Compounds E, to an acetal derivative of a 21-aldehyde, the former is then reacted, according to the process of this invention, under anhydrous conditions in an acidic medium with either a monohydric alcohol of the formula BOH or a dihydric alcohol of the formula B'(OH) wherein B and B are as abovedefined, preferably with an alcohol of the formula BOH, wherein B is a lower alkyl (e.g. methyl, ethyl, n-propyl, or n-butyl.) or benzyl radical. The reaction is preferably carried out by dissolving o'r suspending the starting material in an anhydrous organic solvent, such as chloroform, acetone, dioxane, etc., and treating the solution with a mineral acid such as hydrogen chloride or a strong organic acid, such as trichloroacetic acid or p-toluene sulfonic acid, dissolved in the alcohol reactant. The ratio of alcohol to steroid for the reaction is preferably at least two equivalents of alcohol (i.e. two moles of an alcohol BOH or one mole of an alcohol B(OH) per mole of steroid. If the alcohol reactant isa lower alcohol, the nitrone can be suspended directly in the mineral acidalcohol solution, thereby eliminating the organic solvent.

The reaction'proceeds readily at room temperature, but may be conducted at any temperature in the range of about25 C. to about C.

The acetal derivative formed by this step of the process of this invention may then be converted to the corresponding free aldehyde by reacting the acetal with an aqueous mineral acid, such as hydrochloric acid or perchloric acid, in mixture with an organic solvent, such as aceticacid, dioxane, acetone, etc., preferably at room temperature.

The free aldehydes can also be prepared directly from the nitrones by reacting the latter with the aforementioned mineral acids or strong organic acids, in an inert organic solvent such as acetone, acetic acid, dioxane, etc., preferably at ro'om temperature. These free aldehydes can then in turn be converted to either the acetalized derivatives by treatment with an alcohol, such as those of the formula BOH and B'(OH) under acidic conditions, or the diesterified derivatives by treatment, in an organic base (e.g. pyridine), with an anhydride, such as those of the formula 0 0 ll 1! 0-0113 wherein B is as hereinbefore defined, as exemplified by acetic anhydride.

A modification of the process of this invention consists of the direct oxidation of an acetal derivative of a 21- aldosteroid having an IIB-hydroxy group to the correis then reacted with a customary oxidizing agent, such as sponding acetal derivative having an 11-keto group. chromic oxide in a basic medium such as pyridine, to Thus, to form a 21-a1do steroid having an ll-keto group, oxidize the llfi-hydroxy group to keto, and the ll-keto instead of starting with the corresponding steroid having ZI-acetal derivative thus formed is then converted to the an 11-keto group and convertingthis ll-keto steroid to 5 free 21-aldehyde.

acetal derivative and thence to the free aldehyde, the 1118 For the purpose of illustrating one process of this in hydroxy derivative (R" is hydrogen, R'" is ,B-hydroxy) is ventio'n, reference is made to the following schematic chosen as the initial reactant, and this reactant is conanalysis employing A -pregnane-9B,11 3-oxids-17u,21-diolverted to the 21-aceta1 derivative. The acetal derivative 3,2'O-dione 21 -mesylate as starting material:

The acetal derivatives and the free aldehydes which represent the final products of the processes of this invention are active materials which possess glucocorticoid as well as mineralocorticoid activity. Thus, they can be administered instead of, and in the same manner as, cortisone or hydrocortisone in the treatment of rheumatoid arthritis and dermatomyositis, and desoxycorticosterone in the treatment of Addisons disease or adrenal insufliciencies. The dosage for such administration is of course dependent on the relative activity; thus, where the acetal derivative, for example, has activity of the same order as hydrocortisone, for example, the dosage is of the same order.

The following examples are illustrative of the invention (all temperatures being in centigrade):

EXAMPLE 1 21-br0m0A -pregnene-9,B,1 IB-oxido-I 7a-0l-3,20-dione A solution of 100 mg. of A -pregnene-9B,l1B-oxido- 17u,21-diol-3,20-dione 21-mesylate (I) and 300 mg. of anhydrous lithium bromide in ml. of acetone is refluxed for /2 hour. After removal of the acetone in vacuo the residue is taken up in water and chloroform and the resulting chloroform extract washed with dilute sodium bicarbonate solution and water. After drying over sodium sulfate the chlorofrom solution is evaporated to dryness in vacuo and the resulting crystalline residue recrystallized from acetone. Pure Zl-bromo-A pregnene- 918,1lfl-oxido-l7a-ol-3,20-dione has the following properties: M.P. 193 (dec.); [04],; +18 (0., 0.71 in CHCl mg, 243 mu (6: 16,200); 2.88 5.75 6.06 6.15

Analysis.-Calc. for C21H27O4B1' (423.33): C, 59.58; H, 6.42. Found: C, 59.56; H, 6.74.

EXAMPLE'Z A suspension of A -pregnene-9/3,11B-oxido-17a,21-diol- 3,20,dione 21-mesylate (I) and 300 mg. of lithium chloride in 6 ml. of acetone is refluxed for 2 hours. After removal of the solvent in vacuo the residue is distributed between water and chloroform. The chloroform solution is dried over sodium sulfate and concentrated to dryness in vacuo. The crystalline residue consisting of EXAMPLE 3 21 -bromo-Qa-chloro-M-pregnene-I 1 5,1 7a-di0l- 3,20-di0n'e (V) To a solution of 42 mg. of 2l-bromo-A -pregnene- 95,1lfi-oxido-17u-ol-3,20-dione in 8.4 ml. of alcohol-free chloroform is added, at 0, 1.8 ml. of 0.5 N hydrochloric acid in chloroform. After 60 minutes, ice and dilute bicarbonate are added to wash out excess acid; and after separation of the layers, the chloroform solution is washed with water, dried over sodium sulfate and evaporated to dryness. The crystalline residue is recrystallized twice from acetone to give pure 21-bromo-9a-chloro-A -pregnene-l 1 fl,17a-diol-3,20-dione.

If hydrofluoric acid is substituted for the hydrochloric acid in the procedure of Example 3, 21-bromo-9a-fluoro- M-pregnene-l1,17a-diol, 3,20-dione (IV) is formed.

EXAMPLE 4 Anhydrous hydrogen fluoride is added to a solution of 66 mg. of 21-chloro-A -pregnene-9fi,11fl-oxide-l7a-ol- 3,20-dione in 9.5 ml. of chloroform and 0.5 ml. of alcohol (contained in a polyethylene vessel provided with a copper inlet tube). During the addition, the solution is maintained in an ice bath and agitated by magnetic stirring, until the solution assumes a prominent red color. The inlet tube is then replaced by a polyethylene cap, and the reaction allowed to proceed with stirring for 1.5 hours at 0. Concentrated aqueous sodium bicarbonate solution is then added until the mixture is slightly alkaline, and the two layers are separated. The now light-yellow chloroform solution is washed with water; and after drying over sodium sulfate, it is evaporated to dryness in vacuo. The residue is then taken up in hot ethyl acetate, the resulting suspension filtered, and the filtrate, on cooling, deposits a crystalline precipitate. This material is essentially pure 21 chloro 9a fluoro A pregnene- 1lB,l7a-diol-3,20-dione which is recrystallized from ethyl acetate to give a pure product having the properties described in Example 7.

If hydrochloric acid is substituted for the hydrofluoric acid in the procedure of Example 4, 9oz,21-dichloro A -pregnene-ll/8,l7a-diol-3,20-dione (IX) is formed.

Similarly if hydrobromic or hydroiodic acid is substituted for the hydrochloric or hydrofluoric acid in the procedures of Examples 3 and 4, the corresponding 90:- bromo and 9a-iodo derivatives are formed.

9oz,21 dichloro A pregnene 11,3,l7a diol 3,20- dione (IX) can also be prepared directly from A pregnene 95,115 oxido 17a,21 diol 3,20 dione I lithium chloride in 6 ml. of glacial acetic acid is heated on the steam bath for 30 minutes. After removal of the solvent in vacuo the residue is taken up in ethyl acetate and water. The ethyl acetate layer is extracted with dilute sodium bicarbonate solution and water and dried over sodium sulfate. The solvent is removed in vacuo and the crystalline residue recrystallized from alcohol. Pure 9u,21-dichloro-11B,l7u-diol-3,20-dione has the following properties, M.P. about 275277 (dec.); [a] +156 (c., 0.39 in dioxane);

AEEZ ZSQ 3.04 (OH) 5.83 (ZO-keto) ;6.0 (A -3-ketone) AnaZysis.-Calcd. for C H O Cl (415.34): C, 60.73; H, 6.79; Cl, 17.07. Found: C, 61.01; H, 6.89; Cl, 17.55. The 9a-halo,l1B-hydroxy steroids having a 21-bromo or chloro substituent can also be prepared from the corresponding 2l-alkanesulfonyloxy derivatives as illustrated by the following examples:

EXAMPLE 6 9oz fluoro 21 liromo A pregnene 115,170: diol- 3,20-di0ne (IV) A solution of mg. of 9a-fluorohydrocortisone 2lmesylate and 160 mg. of lithium bromide in 3 ml. of glacial acetic acid is refluxed for /2 hour. The mixture is concentrated in vacuo to small volume and the residue distributed between water and ethyl acetate. The ethyl acetate layer is washed with dilute sodium bicarbonate solution and with water, and dried over sodium sulfate. Evaporation of the solvent in vacuo leaves the 21-bromo 9 compound as a crystalline residue, whichafter recrystal lization from 95% ethanol has'the following properties, M.P. about 252 (dec.); [a] -|140 (c., 0.43 in dioxane); V v I I xylg- 237 my (e=20,000); Ami? 288p, 3.08p. (OH), 5.86

. (2Q-keto), 6.10 .(A -3-ket,0ne)

Analysis.Calcd. for C H OiFBr (443.35): C, 56.89;

H, 6.37; Br, 18.26. Found: C, 56.85; H,-6.37; Br, 18.10.

EXAMPLE 7 9oz fluoro 21 chloro A pregnene 11,8,170: diol- 3,20-dine (VIII mg; 238 1 (e =17,700 x232 2.88 3.03,. on), 5.83,.

(20-keto), am s-1.6mm

Analysis.-Calcd. for C H O FCl (398.89): C, 63.23; H, 7.08; Cl, 8.89. Found: C, 63.25; H, 7.34; Cl, 8.44.

The reactions of Examples 6 and 7 can also be carried out with acetone as the solvent. I

Similarly, by substituting either 9a-chlorohydrocortisone 21-mesylate or 9a-bromohydrocortisone 21- mesylate forthe 9u-fiuorohydrocortisone Z I-mesyl-ate in the procedures of Examples 6 and 7, the corresponding 21-bromo and 21-chloro derivatives are obtained, respectively.

The 9a-halo-1lfl-hydroxy-Zl-bromo or chloro steroids produced by the procedures of Examples 3 through 7 can be oxidized to the corresponding 9op-halO-l1-k6tO-2lbromo or chloro derivatives as illustrated by the following example:

EXAMPLE 8 90a fluoro 21 chloro A pregnene.-- 17a ol 3,11,20-tri0ne (X) To a solution of 100 mg. of 9u-fluoro-2l-chloro-A pregnene-1lfi,l7a-diol-3,20-dione in ml. of glacial acetic acid is added a solution of 40 mg. of'chromic acid in 4 ml. of acetic acid. A half-hour later, 0.5 ml. of methanol is added, and the resulting mixture is concentrated in vacuo. The residue is distributedbetween chloroform and water, and the resulting chloroform extract is washed with water, sodium bicarbonate solution and again with Water. After drying over sodium sulfate and evaporation of the solvents in vacuo, the residue is crystallized from 95 ethanol to give pure 9a-fluoro-2lchloro-A -pregnene-17a-ol-3,11,20-trione. ,1

Similarly, by substituting 9u-fluoro-2l-bromo-A pregnene 115,17ot diol 3,20 dione (IV), 90: chloro- 21 bromo A pregnene 115,170; diol 3,20 dione (V), or 911,21-dichloro-A -pregnene-llp,l7d-diol-3,20- dione (IX)- for" the 9a-fluoro-2l-chloro-A-pregnene- 1'lB,17u-diol-3,20-dione (VIII) in the procedure of'Example 8, 9u-fluor0-2l-bromo-A -pregnene-17a-ol-3,11, 20-trione (VI), 9a-chloro-2l-bromo-A -pregnene-17uol-3,11,20-trione (VII), and 90:,2l-dichloro-A' -pregnenel7a-ol-3,11,20-trione (XI) are obtained, respectively.

The 9a-halo-11fi-hydroxy (or 11-keto)-21-bromo or chloro steroids formed in the procedures of Examples 3 through 8 can be converted to their ZI-pyridinium derivatives as illustrated in the following example:

. EXAMPLE 9 a fluoro A pregnene 1113,17 diol 3,20 dione 21 -pyridinium chloride (XVI) from 9u-fluoro-21- chloro A pregnene 115,170: diol 3,20 dione VIII) A solution of 156 mg. of 9ot-iluoro-2l-chloro-A pregnene-l1/3,17a-diol-3,20-dione in 3 ml. of dry pyridine is heated on the steam bath for 30 minutes and after cooling 5 ml. of acetone is added. Cooling produced a crop of crystals (about 123 mg.), M.P. about 3l932l (dec.) which represent the 21-pyridinium chloride. From the mother liquors about 32 mg. of starting material M.P. 263 (dec.) is recovered.

The 21-pyridinium halides can be prepared directly from the 2l-alkanesulfonyloxy derivatives as illustrated by the following two examples:

EXAMPLE 10 9a-flu0ro-11fl,1 7 a-dihydroxyprogesterone 21 pyridinium chloride (XVI) from 9a-fluorohydrocortisone 21-mesylate A solution of 500 mg. of 9ot-fluorohydrocortisone 21- mesylate in 5 ml. of anhydrous pyridine is heated on the steam bath for 30 minutes. To this solution which contained 9a-fluoro-A -pregnene 11,8,l7a-diol-3,20-dione-2lpyridinium mes'ylate is added after cooling 3 ml. of 2% methanolic hydrogen chloride and "shortly thereafter 20 ml. of acetone. Crystallization of 9a-fluoro-A -pregnenel1B,17a-diol-3,20-dione 21-pyridinium chloride ensues rapidly and is complete after several hours in the refrigerator.

The resulting crystals are filtered oif and washed with acetone. Recrystallization from methanol furnishes the pure 21 pyridinium chloride, M.P. about 320321 (dec.); [M +200 (c., 0.22 in methanol);

Analysis.--Ca1cd. for C2GH3304NC'IF C, 65.33; H, 6.96; Cl, 7.42. Found: C, 65.48; H, 6.82; Cl, 7.37.

Following the procedure of Example 9, by substituting 9a -fluoro-21-bromo-A +pregnene-1 1 3,17u-di01-3,20 dione (IV), 9u-chloro-21bromo-A -pregnene-1 1fl,17a-di0l-3,20- dione (V), 9u-fluoro-2l-bromo-A -pregnene'17a-ol-3,11, 20-trione (VII), 9a,2l-dichloro-A -pregnene-l1,8,17u-diol- 3,20-dione (IX), 9a-fluoro-21-chloro-A -pregnene-l7a-ol- 3,11,20-trione (X), and 9a,21-dich1oro-A -pregnene-17a- 3,11,20-trione (XI) for the 9a-fluoro-2l-chloro-A pregnene-11fi,l7u-diol-3,20-dione, there is obtained Compounds XII, XIII, XIV, XV, XVII, XVIII, and XIX, respectively.

Compounds XII through XIX can also, be prepared directly from the corresponding 9u-halohydrocortisone or 9ot-ha1ocortisone by reaction thereof with p-toluenesulfonyl chloride or bromide in anhydrous pyridine at an elevated temperature as illustrated by the following example:

EXAMPLE 11 9a-chl0ro-A -pregnene-115,17a-diol-3,20-di0we 21 pyridinium chloride (XVII) and 9u,21-dichlor0-A -preg- Irene-115,17ot-di0l-3,20-di0ne (IX) from 9a-chl0r0hydrocortisone v r an additional crop of this substance and then two crops $51} 241 m (e=16,000); mg

11 of a lower melting substance, M.P. about 235-237, which is recrystallized from 95% alcohol. The latter substance represents 9a,2l-dichloro-M-pregnene 11,9,1701- diol-3,20-dione; [M +178 (c., 0.28 in absolute alcohol);

2.87; (ll-OH), 3.01;; (17-OH), 583 (20-keto), 6.08 1 (3-keto) Analysis.-Calcd. for C H O Cl (415.34): C,' 60.72; H, 6.79; 01, 17.08. Found: C, 60.79; H, 6.70; C1, 1666.

If p-toluenesulfonyl bromide is substituted for ptolu'enesulfonyl chloride in Example 11, the resulting mixture will consist of the 2l-pyridinium bromide (XIII) and the 21-bromide (V). Furthermore, upon the substitution of 9a-chlorocortisone for the 9a-chloro-hydrocortisone, either a mixture of 9ot-chloro-A -pregnene-17mol-3,1l,20-trione 21 pyridinium'chloride (XIX) and 9a,21- dichloro-A -pregnene-17a-ol-3,11,20-trione (XI), or 9achloro-M-pregnene-1711-01-3,11,20-trione 21 pyridinium bromide (XV) and 9ot-chloro-21bromo-A -pregnene-l7uol-3,l1,20-trione (VII), depending on whether tosyl chloride or tosyl bromide is used, will be formed.

Since the tertiary base is eliminated in the next step of the process, the exact chemical composition of the base is of no importance, so that any other tertiary base may be substituted for pyridine in the processes of the above Examples9, 10, and 11 to yield other quaternary ammonium salts. Examples of such bases include the lutidines, the collidines, the tri(lower alkyl)amines (e.g. trimethylamine and triethylamine), N-alkylated piperidine,-

EXAMPLE l2 Qa-fluoro-M-pregnene-I1,9,l7a-diol-3,20-dione 21 (p-dimethylaminophenyl) -nitrone (XX) from QOL flUOIO-A pregnene 11,6,17a-diol-3,20-dione-21-pyridinium chloride (XVI) To a warm solution of 250 mg. (0.52 millimole) of 9a-fluoro A pregnene-1 15,17a-diol-3 ,20-dione 21-pyridinium chloride in 7 ml. of methanol and 4.5 ml. water is added 89 mg. (0.58 millimole) of p-nitrosodimethyl aniline and shortly thereafter a solution of 55 mg. of potassium bicarbonate (0.55 millimole) in 0.7 ml. of water. The mixture is gently warmed on a steam bath and then allowed to remain in the refrigerator overnight. The resulting red crystals (about 170 mg.) are filtered on, washed with 1:1 methanol-water and the mother liquors concentrated in vacuo. An additional crop (about 47 mg.) is obtained in this manner. The nitrone'is used in the preparation ofthe aldehyde without further purification. For analysis the unstable nitrone is recrystallized from methanol, M.P. about 226? (dec.);

A7,}; 240 my (e=25,000), 304 m (e=9,400) and415 my.

6 12,8 Anaiysis.Calcd. for C H O N F (512.61): C, 67.94; H, 7.28; N, 5.47. Found: C, 68.87; H, 7.36; N,

6.28. e I I 1 EXAMPLE 13' 9a-chloro-M-firgnene-I1B,]7ot-di0l-3,20 dione 21 (p-dimethyl-aminophenyl)-nitrne (XXI) from 9a-chloro- M-pregnene-I 1 5,] 7oz diol 3,20 dione 21 -pyridinium chloride (XVII) To a warm suspension of 140 mg. of 9m-chloro-A -pregnene-1 lfi,l7u-diol 3,20-dione 21 pyridinium chloride in 3.8 ml. of methanol and 2.4 ml, water is added 47 mg. of p-nitrosodimethyl aniline. When the latter has dissolved a solution of 30 mg. of potassium bicarbonate in 0.38 ml. of water is added and the mixture warmed on the steam bath until all the pyridinium salt has dissolved,

and has been replaced by the red crystals of the nitrone. The reaction mixture is then cooled and allowed to remain in the refrigerator for one hour. The crystals are filtered and washed with 50% methanol-water and finally with water. The yield of nitrone is about 104 mg, M.P. about 206. The substance is used in the preparation of the aldehyde without further purification.

In an analogous manner the pyridinium bromides (XII and XIII) can be converted to the 9oc-flUOI0 and 9a-chloro derivatives, respectively.

If 9u-fiuoro-A -pregnene-17ot-ol-3,11,20-trione 2l-pyridinium chloride (XVIII) of bromide (XIV) is substituted for the pyridinium chloride in Example 12, 9a-fluoro-A pregnene 17 a ol 3,11,20-trione 2l-(p-dimethylaminophenyl)-nitrone (XXII) is formed. Similarly, if chloro-A -pregnene-17u-ol-3,11-20-trione 21 pyridinium chloride (XIX) or bromide (XV) is substituted for the pyridinium chloride in Example 13, 9a-chloro-A -pregnene-17a-ol-3,1 1,20-trione 21-(p-dimethylaminophenyl) nitrone (XXIII) is produced. Analogously, the quaternary ammonium salts of the corticosterone and dehydrocorticosterone derivatives are converted to the corresponding nitrones. I

Although the above examples employ p-nitrosodimethyl aniline as the source of the nitroso radical, any other aromatic nitroso-containing compound (such as nitroso benzene) may be used instead, since in the next step of the process the nitroso group is replaced by an aldo or acetalized aldo substituent.

The nitrone is then converted either to the 21-acetalized aldo or the free 2l-aldo as illustrated by the following examples:

EXAMPLE 14 9a fluoro-M-pregnegne-I 118,1 7u-diol-3,20-di0ne-2I -al-hy drate (XXIV) from 9a-flu0ro-A -pregnene-I15,170:- dz'ol-3,20-dione 21 -(p dimethylaminophenyl) -nitr0ne To a suspension of mg. of 9a-fluoro-A -pregnene- 1lfl,l7a-diol-3,20-dione (21 p dimethylaminophenyl nitrone in 2 ml. of acetone is added at room temperature 1 ml. of 2 N aqueous hydrochloric acid. Gentle agitation causes the nitrone to dissolve rapidly to form a yellow solution. After centrifugation of some insoluble matter 4 ml. of water is added, which causes the aldehyde hydrate to crystallize in fine needles. After one hour at 5 the crystals are separated from the mother liquors and washed thoroughly with water. The resulting crystals (about 81.5 'mg.), after recrystallization from acetone- Water melt at about l9l, M1 l26 (c., 0.48 in methanol); 7 x 3; 238mg (e=18,300); k553i? 3.0-3.2,a (OH), 5.86

. (20 keto),.615 (4-keto) A nalysis. Calcd. for C21H27O5F'H2O (396.44): C, 63.62; H, 7.37; F, 4.79. Found: C, 63.71; H, 7.18; F, 4.87.

9a fluoro-A -pregnenel 15,l7a-diol-3,20-dioee-21-ol hydrate'possesses about /3 the activity of cortisone acetate in the'ratliver glycogen assay and is about equal in activity to desoxycorticosterone in the sodium retention assay in the rat. v p

' EXAMPLE 15 p 909- chloro-Af -pregnen e-lIB,17udi0l-3,20-di0ne-2I -al hyirate (XXV) from Qua-chloro-M-pregnene-I15,17a-

diol 3,20 dione-ZJ-(p dimethylaminophenyl)-nilr0ne 90: chloro-M-pregnene-l lB,l7a-di0l-3,20-dione 2l-(-pdimethylaminophenyl)-nitrone is converted to 9a-chloro- M-pregnene-llfl,l7a-diol-3,20-dione-21-al hydrate as described in Example 14 for the corresponding fiuoro compound 7 The pure 9a-chloro-A -pregnene 115,17a diol 3,20- dione-Zl-al hydrate, after recrystallization from dilute 13 acetone, has the following properties: M.P. greater than 345 with darkening at 195; [121 +132 (c., 0.35 in methanol); mg, 240 m (e=18,400) mg? 2.92 3.05-3.09 (OH), 5.85;; (ZO-keto), 6121.1 (3-keto) Analysis.-Calcd. for C21H27O5C1'H2O (412.90): C,

61.08; H, 7.08; Cl, 8.59. Found: C, 61.43; H, 6.73; Cl,

9a-chloro-A -pregnene-115,17a-diol- 3,20- dione 21 al hydrate shows about A the activity of cortisone acetate in the rate liver glycogen assay. It is about 3 times as active as desoxy-corticosterone in the sodium retention assay in the rat.

If 9a-fluoro-A -pregnene-17u-ol-3,11,20-trione 21-(p-dimethylaminophenyl)-nitrone (XXII) is substituted for the 9a-fluoro-A -pregnene-l1 8,17a-diol-3,20-dione 21-(pdmethylamino-phenyl)-nitrone of Example 14, or if 912- chloro-A -pregnene-1711-01-3 ,1 1,20-trione 21-(p-dimethylaminophenyl)-nitrone (XXIII) is substituted for the 9mchloro-llb-hydroxy derivative of Example 15, then 90:- fiuoro-A' -pregnene-17x-ol-3,11,20-trione 21 al hydrate (XXVI) and 9u-chloro-A -pregnene-l7a-ol-3,l1,20-trione- 21-al hydrate (XXVII) are formed, respectively. Similarly, by substituting the 21-(p-dimethylaminophenyl)- nitrone derivatives of 9oc-fil1010 (or chloro)-M-pregnene- 11fi-ol-3,20-dione, or of 9a-fluoro (or chloro)-M-pregrene-3,11,20-trione, or of 9u-fluoro (or chloro)-A pregnene-llB-ol-lS-al for the nitrone employed in Example 14, 90c fluoro(or chloro) A pregnene 11;.9-01- 3,20-dione-21-al hydrate, and 9a-fluoro(or chloro)-A pregnene-l1fi-ol-3,20-dione-18,21-diol ZI-hydrate, respectively, are produced.

The 21-acetals can be produced directly from the nitrones as illustrated by the following example:

EXAMPLE 16 9a-fluoro-A -prPgnene-I1B,I7a-di0l-3,20-di0ne 21 -al dimethyl-acetal (X X VIII from 9a-fluoro-A -pregnene- 11 8,] 7 a diol-3,20-dine-21-(p-dimethylaminophenyl) nitrone (XX) To a suspension of 120 mg. of 9a-fluoro-A -pregnene- 115,170: diol 3,20 dione-2l-(p-dimethylaminophenyl)- nitrone in 2 ml. of acetone is added at room temperature 1 ml. of 2 N methanolic hydrogen chloride. The mixture is taken up in 20 ml. of chloroform and 4 m1. of water. After separation of the phases, the chloroform layer is extracted with dilute bicarbonate and water and after drying over sodium sulfate, is evaporated to dryness in vacuum. The resi ue represents the dimethyl acetal of 9a-fluoro-A -pregnene-1 1p,18u-diol-3,20-dione-2 l-al.

Similarly, by substituting 9a-ehloro-A -pregnene-11B, 17ot-di0l-3,20-dione-2l-(p-dimethylaminophenyl) nitrone (XXI), 9a fluoro-A -pregnene-17a-ol-3,1 1,20-trione-21- (p-dimethylaminophenyl)-nitrone (XXII), or 9a'chlor0- A pregnene-17a-ol-3,11,20-trione-2l-(p-dimethyl-aminophenyD-nitrone (XXIII) for the nitrone of Example 16, the respective 21-dimethyl acetals, XXIX, XXX, and XXXI, are produced. Furthermore, if 1% ethanolic hydrogen chloride is substituted for the methanolic hydrogen chloride in the procedure of Example 16, the corresponding diethyl acetals are formed.

The invention may be variously otherwise embodied within the scope of the appended claims.

We claim:

1. A steroid of the general formula wherein at least one and not more than two of the positions 1,2; 4,5; and 6,7 is double-bonded, R" is hydrogen, R is fi-hydroxy and together R" and R' is keto, Z is selected from the group consisting of hydrogen and 0:- hydroxy, X is halogen, and W is a monocyclic aromatic radical.

2. 9a-halo-A -pregnene-l1p,17a-diol 3,20-dione 21-(pdimethylaminophenyl)-nitrone.

, dimethylaminophenyl)-nitrone.

. 4. 9a-Chl0rO-A -p1'egnene-l1fl,17a-di01-3,20-(H0116 21- (p-dimethylaminophenyl)-nitrone.

References Cited in the file of this patent UNITED STATES PATENTS 2,268,084 Reichstein Dec. 30, 1941 2,664,428 Miescher Dec. 29, 1953 2,665,274 Conbere Jan. 5, 1954 2,707,111 Hogg et a1. May 3, 1955 2,708,202 Pfister et al May 10, 1955 2,720,523 MacPhillamy Oct. 11, 1955 2,730,525 Hogg Jan. 10, 1956 2,752,372 Reichstein June 26, 1956 2,759,929 Farrar Aug. 21, 1956 UNITED STATES PATENT OFFICE Certificate of Correction Patent No. 2,920,084; January 5, 1960 Josef Fried et a1.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction and that the said Letters Patent should read as corrected below.

Column 2, line 54, for 21-free oil steroid read -21-free o1 steroid; column 12, line 58, for -3,20-dioee-21-01 read -3,20-dione-21-o1; column 13, line 11, for the rate liver read the rat liver; line 21, for chloro-llb-hydroxy read ch1oro-11flhydroxy.

Signed and sealed this 28th day of June 1960.

[SEAL] Attest:

KARL H. AXLINE, ROBERT C. WATSON,

Attestz'ng Ofiicer. Commissioner of Patents. 

1. A STEROID OF THE GENERAL FORMULA 